Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure.
OBJECTIVE
We 1) evaluated whether interleukin-6 (IL-6) is produced in the peripheral circulation in patients with congestive heart failure (CHF), 2) estimated the factors for increased IL-6, and 3) clarified the prognostic role of high plasma levels of IL-6 in patients with CHF.


BACKGROUND
Although plasma levels of IL-6 have been reported to increase in patients with CHF, and production of IL-6 in endothelial cells and vascular smooth muscle cells has been postulated from in vitro studies, the origin of the increase of IL-6 in CHF remains unknown. Moreover, the prognostic value of a high plasma level of IL-6, independent of classic neurohumoral factors, remains to be elucidated.


METHODS
A comparison was made of the plasma levels of IL-6 between the femoral artery and the femoral vein in 13 normal subjects and in 80 patients with CHF. In another study, we measured plasma IL-6 in 100 patients with CHF and follow-up data.


RESULTS
Plasma IL-6 levels increased significantly from the femoral artery to the femoral vein in normal subjects and in patients with CHF. Arteriovenous IL-6 spillover in the leg increased with the severity of CHF. Among the hemodynamic variables and the various neurohumoral factors, the plasma norepinephrine (NE) level showed an independent and significant positive relation with the plasma IL-6 level in patients with CHF. Moreover, treatment with beta-adrenergic blocking agents showed an independent and significant negative relation with plasma IL-6 levels. In 100 patients, plasma IL-6 (p < 0.0001), NE (p = 0.0004) and left ventricular ejection fraction (0.015) were significant independent prognostic predictors by Cox proportional hazards analysis.


CONCLUSIONS
Our findings indicate that the IL-6 spillover in the peripheral circulation increases with the severity of CHF and that the increase in plasma IL-6 is mainly associated with the activation of the sympathetic nervous system. High plasma levels of IL-6 can provide prognostic information in patients with CHF, independent of left ventricular ejection fraction and plasma NE, suggesting an important role for IL-6 in the pathophysiology of CHF.
Tsutamoto
T
T
First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Japan. tutamoto@belle.shiga-med.ac.jp
Hisanaga
T
T
Wada
A
A
Maeda
K
K
Ohnishi
M
M
Fukai
D
D
Mabuchi
N
N
Sawaki
M
M
Kinoshita
M
M
D000316:Adrenergic alpha-Agonists / Q000097:blood; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D009320:Atrial Natriuretic Factor / Q000097:blood; D016022:Case-Control Studies; D019332:Endothelin-1 / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005263:Femoral Artery; D005268:Femoral Vein; D005500:Follow-Up Studies; D005544:Forecasting; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D011379:Prognosis; D016016:Proportional Hazards Models; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013564:Sympathetic Nervous System / Q000503:physiopathology; D013566:Sympathomimetics / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014662:Vasoconstrictor Agents / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D019332:Endothelin-1; D015850:Interleukin-6; D018377:Neurotransmitter Agents; D013566:Sympathomimetics; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D009320:Atrial Natriuretic Factor; D009638:Norepinephrine